tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting <i>PCSK9</i> in Nonhuman Primate and Mouse Models
Authors: Richard G. Lee, Anne Marie Mazzola, Maurine C. Braun, Colin Platt, Scott B. Vafai, Sekar Kathiresan, Ellen Rohde, Andrew M. Bellinger, Amit V. Khera
Journal: Circulation (2022)

VERVE-101 is an investigational in vivo CRISPR base-editing medicine designed to alter a single DNA base in the PCSK9 gene, permanently turn off hepatic protein production, and thereby durably lower low-density lipoprotein cholesterol. We test the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of nonhuman primates and a murine F1 progeny study.Cynomolgus monkeys were given a single intravenous infusion of a vehicle control (n=10) or VERVE-101 at a dose of 0.75 mg/kg (n=4) or 1.5 mg/kg (n=22) with subsequent follow-up up to 476 days. Two studies assessed the potential for germline editing, including sequencing sperm samples from sexually mature male nonhuman primates treated with VERVE-101 and genotyping offspring from female mice treated with the murine surrogate of VERVE-101 (VERVE-101mu).Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg, respectively. This translated into mean reductions in blood PCSK9 (proprotein convertase subtilisin/kexin type 9) of 67% and 83% and reductions of low-density lipoprotein cholesterol of 49% and 69% at the 0.75 and 1.5 mg/kg doses, respectively, assessed as time-weighted average change from baseline between day 28 and up to 476 days after dosing. Liver safety monitoring noted a transient rise in alanine aminotransferase and aspartate aminotransferase concentrations after infusion that fully resolved by day 14 with no accompanying change in total bilirubin. In a subset of monkeys necropsied 1 year after dosing, no findings related to VERVE-101 were identified on macroscopic and histopathologic assessment of the liver and other organs. In the study to assess potential germline editing of male nonhuman primates, sperm samples collected after VERVE-101 dosing showed no evidence of PCSK9 editing. Among 436 offspring of female mice treated with a saturating dose of VERVE-101mu, the PCSK9 edit was transmitted in 0 of 436 animals.VERVE-101 was well tolerated in nonhuman primates and led to 83% lower blood PCSK9 protein and 69% lower low-density lipoprotein cholesterol with durable effects up to 476 days after dosing. These results have supported the initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease.
Racial and Ethnic Disparities in Outpatient Treatment of COVID-19 ― United States, January–July 2022
Authors: Tegan K. Boehmer, Emily H. Koumans, Elizabeth L. Skillen, Michael D. Kappelman, Thomas W. Carton, Aditiben Patel, Euna M. August, Ryan Bernstein, Joshua L. Denson, Christine Draper, Adi V. Gundlapalli, Anuradha Paranjape, Jon Puro, Preetika Rao, David A. Siegel, William E. Trick, Chastity L. Walker, Jason P. Block
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

COVID-19 patients were identified by a positive SARS-CoV-2 viral test result, an ICD-10-CM diagnostic code for COVID-19 (U07.1 and U07.2), or treatment with a COVID-19 medication (Paxlovid, Lagevrio, monoclonal antibodies, or Veklury).Patients were considered treated if they were prescribed Paxlovid.† Race and ethnicity were assessed as separate variables because the PCORnet distributed query statistical program does not allow for assessment of combined race and ethnicity by month.Among 7,631 patients of AIAN/NHOPI race, 67% were AIAN and 33% were NHOPI.Among 38,447 patients of multiple or other race, 19% were multiple race and 81% were other race; 58% of multiple and other race patients were of Hispanic ethnicity.Abbreviations: AIAN/NHOPI = American Indian or Alaska Native and Native Hawaiian or other
Cetuximab Responses in Patients with HNSCC Correlate to Clonal Expansion Feature of Peripheral and Tumor-Infiltrating T Cells with Top T-Cell Receptor Clonotypes
Authors: Huaibin Ge, Robert L. Ferris, Jing H. Wang
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Cetuximab is a standard-of-care treatment for head and neck squamous cell carcinoma (HNSCC). Well-defined correlative markers of therapeutic responses are still lacking. Characterizing dynamic changes of T-cell receptor (TCR) repertoire in peripheral blood and tumor tissue may facilitate developing markers for cetuximab response in HNSCCs. Experimental Design: We analyzed high-throughput TCRβ sequencing data generated with ImmunoSEQ platform using peripheral blood mononuclear cells (PBMC) and tumor-infiltrating lymphocytes (TIL) from patients with HNSCC before and after cetuximab treatment (pre-/post-PBMC vs. pre-/post-TIL). Multiple analytic approaches were employed to normalize sequencing data. Results: Normalized TCR richness was significantly lower in post-TIL than pre-TIL, suggesting that cetuximab reduced TCR diversity and promoted TCR expansion in TIL samples, regardless of response status. The magnitude of clonal expansion (defined as expansion rate) in top 20 TCR clonotypes was significantly higher in responder PBMC with or without normalization, and in responder TIL upon normalization, than nonresponder ones. Notably, the expanded top 20 or top 50 TCR clonotypes overlapped between PBMC and TIL samples, which occurred significantly more frequently in responders than nonresponders. Conclusions: Patients with cetuximab-treated HNSCC harbor dynamic changes of TCR repertoires correlative to therapeutic responses. The expansion rate of top TCR clonotypes in peripheral blood may serve as a minimally invasive, readily accessible, and feasible marker for predicting cetuximab responses in HNSCCs and beyond, and the expansion rate of top TCR clonotypes in TILs and their overlapping probability between PBMC and TIL may serve as additional predictive markers. Our study also highlights the importance of data normalization for TCR repertoire analysis.
Migraine and Mental Health in Pediatrics
Authors: Jessica Hauser Chatterjee, Heidi K. Blume
Journal: JAMA Pediatrics (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Gene Fusion Detection and Characterization in Long-Read Cancer Transcriptome Sequencing Data with FusionSeeker
Authors: Yu Chen, Yiqing Wang, Weisheng Chen, Zhengzhi Tan, Yuwei Song, Herbert Chen, Zechen Chong
Journal: Cancer Research (2022)

Abstract Gene fusions are prevalent in a wide array of cancer types with different frequencies. Long-read transcriptome sequencing technologies, such as PacBio, Iso-Seq, and Nanopore direct RNA sequencing, provide full-length transcript sequencing reads, which could facilitate detection of gene fusions. In this work, we developed a method, FusionSeeker, to comprehensively characterize gene fusions in long-read cancer transcriptome data and reconstruct accurate fused transcripts from raw reads. FusionSeeker identified gene fusions in both exonic and intronic regions, allowing comprehensive characterization of gene fusions in cancer transcriptomes. Fused transcript sequences were reconstructed with FusionSeeker by correcting sequencing errors in the raw reads through partial order alignment algorithm. Using these accurate transcript sequences, FusionSeeker refined gene fusion breakpoint positions and predicted breakpoints at single bp resolution. Overall, FusionSeeker will enable users to discover gene fusions accurately using long-read data, which can facilitate downstream functional analysis as well as improved cancer diagnosis and treatment. Significance: FusionSeeker is a new method to discover gene fusions and reconstruct fused transcript sequences in long-read cancer transcriptome sequencing data to help identify novel gene fusions important for tumorigenesis and progression.
Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma
Authors: Haowen Jiang, Rachel L. Greathouse, Sarah Jane Tiche, Man Zhao, Bo He, Yang Li, Albert M. Li, Balint Forgo, Michaela Yip, Allison Li, Moriah Shih, Selene Banuelos, Meng-Ning Zhou, Joshua J. Gruber, Erinn B. Rankin, Zhen Hu, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye
Journal: Cancer Research (2022)

Abstract The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the NAD+/NADH and pyruvate/lactate ratios and also the α-ketoglutarate/2-hydroxyglutarate (2-HG) ratio. Consequently, NEN treatment induced promoter CpG island demethylation and epigenetic landscape remodeling, activating the neural differentiation program. In addition, NEN treatment upregulated p53 but downregulated N-Myc and β-catenin signaling in neuroblastoma cells. Importantly, even under hypoxia, NEN treatment remained effective in inhibiting 2-HG generation, promoting DNA demethylation, and suppressing hypoxia-inducible factor signaling. Dietary NEN intervention reduced tumor growth rate, 2-HG levels, and expression of N-Myc and β-catenin in tumors in an orthotopic neuroblastoma mouse model. Integrative analysis indicated that NEN treatment upregulated favorable prognosis genes and downregulated unfavorable prognosis genes, which were defined using multiple neuroblastoma patient datasets. Altogether, these results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma. Significance: Targeting cancer metabolism using the mitochondrial uncoupler niclosamide ethanolamine leads to methylome reprogramming and differentiation in neuroblastoma, providing a therapeutic opportunity to reverse the Warburg effect and suppress tumor growth. See related commentary by Byrne and Bell, p.167
Almost All “Natural” Skin Care Products Contain Contact Allergens
Authors: Anita Slomski
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Autologous Gene Therapy Approved for Childhood CALD
Authors: Howard D. Larkin
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Locally delivered modified citrus pectin - a galectin-3 inhibitor shows expected anti-inflammatory and unexpected regeneration-promoting effects on repair of articular cartilage defect
Authors: Yiyun Zhang, Danning Su, Yimeng Wang, Ziqiang Wang, Ying Ren, Rui Liu, Bo Du, Ruiping Duan, Yanping Shi, Lingrong Liu, Xuemin Li, Qiqing Zhang
Journal: Biomaterials (2022)
Association of Gonadotropin-Releasing Hormone Analogue Use With Subsequent Use of Gender-Affirming Hormones Among Transgender Adolescents
Authors: Andrea L. Nos, David A. Klein, Terry A. Adirim, Natasha A. Schvey, Elizabeth Hisle-Gorman, Apryl Susi, Christina M. Roberts
Journal: JAMA Network Open (2022)

Importance Gonadotropin-releasing hormone analogue (GnRHa) use during puberty improves mental health among transgender and gender-diverse (TGD) adolescents. In previous studies, most (96.5%-98.1%) TGD adolescents who started GnRHa subsequently started gender-affirming hormones (GAH), raising concerns that GnRHa use promotes later use of GAH. Objective To determine whether GnRHa use among TGD adolescents is associated with increased subsequent GAH use. Design, Setting, and Participants This is a retrospective cohort study of administrative records collected between 2009 and 2018. The current analysis was completed in August 2022. Participants were enrolled in the US Military Healthcare System (MHS) with an initial TGD-related encounter occurring between ages 10 and 17 years. Exposures GnRHa use. Main Outcomes and Measures Initiation of GAH. Results The 434 patients were a mean (SD) of 15.4 (1.6) years old at the time of their first TGD-related encounter; 312 (71.9%) were assigned female at birth, and 300 (69.1%) had an enlisted insurance sponsor. GnRHa use was more common among patients who were assigned male at birth (28 patients [23.0%]) than those assigned female (42 patients [13.5%]), but GAH use was not. Socioeconomic status was not associated with GnRHa or GAH use. Compared with older patients (aged 14-17 years), those who were younger (aged 10-13 years) at the time of the initial TGD-related encounter had a higher rate of GnRHa use (32 patients [57.1%] vs 38 patients [10.1%]) and a longer median time to starting GAH. The median interval from the date of the initial encounter to starting GAH decreased over time, from 2.3 years (95% CI, 1.7-2.8 years) between October 2009 and December 2014 to 0.6 years (95% CI, 0.5-0.6 years) between September 2016 and April 2018. Patients who were prescribed GnRHa had a longer median time to starting GAH (1.8 years; 95% CI, 1.1-2.4 years) than patients who were not (1.0 years; 95% CI, 0.8-1.2 years) and were less likely to start GAH during the 6 years after their first TGD-related encounter (hazard ratio, 0.52; 95% CI, 0.37-0.71). Among 54 younger (aged 10-13 years) patients who were not eligible to start GAH at their first encounter, GnRHa use was associated with a longer median time to starting GAH, but age at the first TGD-related visit was not. Conclusions and Relevance In this cohort study of TGD adolescents, GnRHa use was not associated with increased subsequent GAH use. These findings suggest that clinicians can offer the benefits of GnRHa treatment without concern for increasing rates of future GAH use.
Adverse Maternal and Delivery Outcomes in Children and Very Young (Age ≤13 Years) US Adolescents Compared With Older Adolescents and Adults
Authors: Beth L. Pineles, Anthony D. Harris, Katherine E. Goodman
Journal: JAMA (2022)

This study uses a US claims database to compare morbidity and delivery outcomes among pregnant 10- to 13-year-olds vs 14- to 17-year-olds and 18- to 19-year-olds.
Experimental Epidemiology
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Validity of the Single-Item Screen–Cannabis (SIS-C) for Cannabis Use Disorder Screening in Routine Care
Authors: Theresa E. Matson, Gwen T. Lapham, Jennifer F. Bobb, Malia Oliver, Kevin A. Hallgren, Emily C. Williams, Katharine A. Bradley
Journal: JAMA Network Open (2022)

Importance Cannabis use is prevalent and increasing, and frequent use intensifies the risk of cannabis use disorder (CUD). CUD is underrecognized in medical settings, but a validated single-item cannabis screen could increase recognition. Objective To evaluate the Single-Item Screen–Cannabis (SIS-C), administered and documented in routine primary care, compared with a confidential reference standard measure of CUD. Design, Setting, and Participants This diagnostic study included a sample of adult patients who completed routine cannabis screening between January 28 and September 12, 2019, and were randomly selected for a confidential survey about cannabis use. Random sampling was stratified by frequency of past-year use and race and ethnicity. The study was conducted at an integrated health system in Washington state, where adult cannabis use is legal. Data were analyzed from May 2021 to March 2022. Exposures The SIS-C asks about frequency of past-year cannabis use with responses (none, less than monthly, monthly, weekly, daily or almost daily) documented in patients’ medical records. Main Outcomes and Measures The Diagnostic and Statistical Manual , Fifth Edition ( DSM-5 ) Composite International Diagnostic Interview–Substance Abuse Module (CIDI-SAM) for past-year CUD was completed on a confidential survey and considered the reference standard. The SIS-C was compared with 2 or more criteria on the CIDI-SAM, consistent with CUD. All analyses were weighted, accounting for survey design and nonresponse, to obtain estimates representative of the health system primary care population. Results Of 5000 sampled adult patients, 1688 responded to the cannabis survey (34% response rate). Patients were predominantly middle-aged (weighted mean [SD] age, 50.7 [18.1]), female or women (weighted proportion [SE], 55.9% [4.1]), non-Hispanic (weighted proportion [SE], 96.7% [1.0]), and White (weighted proportion [SE], 74.2% [3.7]). Approximately 6.6% of patients met criteria for past-year CUD. The SIS-C had an area under receiver operating characteristic curve of 0.89 (95% CI, 0.78-0.96) for identifying CUD. A threshold of less than monthly cannabis use balanced sensitivity (0.88) and specificity (0.83) for detecting CUD. In populations with a 6% prevalence of CUD, predictive values of a positive screen ranged from 17% to 34%, while predictive values of a negative screen ranged from 97% to 100%. Conclusions and Relevance In this diagnostic study, the SIS-C had excellent performance characteristics in routine care as a screen for CUD. While high negative predictive values suggest that the SIS-C accurately identifies patients without CUD, low positive predictive values indicate a need for further diagnostic assessment following positive results when screening for CUD in primary care.
Patient Characteristics and Postoperative Mortality in Children Undergoing Tonsillectomy
Authors: Guan-Jiang Huang, Xue-Sen Yang, Biao-Qing Lu
Journal: JAMA (2022)

To the Editor A recent article1 explored the association of patient characteristics with postoperative mortality in children undergoing tonsillectomy in 5 US states. As otolaryngologists, we are concerned that the authors did not determine the cause of death, especially tonsillectomy-specific death.
Meningeal macrophages protect against viral neuroinfection
Authors: Julie Rebejac, Elisa Eme-Scolan, Laurie Arnaud Paroutaud, Sarah Kharbouche, Matei Teleman, Lionel Spinelli, Emeline Gallo, Annie Roussel-Queval, Ana Zarubica, Amandine Sansoni, Quentin Bardin, Philippe Hoest, Marie-Cécile Michallet, Carine Brousse, Karine Crozat, Monica Manglani, Zhaoyuan Liu, Florent Ginhoux, Dorian B. McGavern, Marc Dalod, Bernard Malissen, Toby Lawrence, Rejane Rua
Journal: Immunity (2022)